When mitochondrial disease is caused
by nuclear DNA mutations, the symptoms and their severity
are very consistent within families. But symptoms can vary
widely even within the same family if the disease is caused
by an mtDNA mutation.
No one knows this better than the Haas family of Charlotte,
N.C. Jonathan, 11; Timothy, 9; and their mother, Sandra, all
have a mitochondrial encephalomyopathy with maternal
The Downs Family
Sandra Haas never knew that she had a mitochondrial
disorder until the disease was diagnosed in her first
biological son, Jonathan. Now she can make sense of symptoms
she only vaguely understood before.
"It's hard to explain," she says, "but I
have a hard time if I walk a distance, like if I'm trying to
go through the airport. If I push myself, I just have to
totally stop or my legs are just going to go out from under
In contrast, Jonathan has more severe muscle weakness in
his legs. He uses a wheelchair to travel more than a short
distance, and he gets muscle cramps at night when he has
overexerted himself during the day.
In Timothy, on the other hand, the disease seems to have
affected his brain more than his muscles.
"Timothy is very bright and personable," says
Haas. "He's never met a stranger. And he can hear a
song and sing it, or he can watch something on TV and tell
you exactly what was said. But in school he just can't get
the simple things like the ABCs."
Heteroplasmy -- the variation of mutations among copies of
mtDNA within a cell -- may account for the very different
symptoms in members of the same family.
DiMauro explains that when you have a mutation in mtDNA,
all cells in the body will contain the mutated DNA, and, in
theory, all tissues should be affected.
"But," says DiMauro, "the trick is in the
percentage of mutant mitochondria in each tissue. Because
different tissues have different energy needs, the
percentage of the mutation needed to cause problems varies."
This phenomenon is called the threshold effect.
"For example, if 70 percent of the mtDNA in the liver
is mutated, that liver may still function pretty well
without causing any symptoms. But the same percent in brain,
or in muscle, may cause problems," he says. Thus, brain
and muscle can be said to have a low threshold for
tolerating mitochondrial mutations.
The idea of an energy threshold explains the variability in
clinical presentation of people with mitochondrial diseases,
even in the same family. It also explains why these diseases
are multisystemic syndromes, DiMauro says.
In other words, even though the two Haas boys got exactly
the same mtDNA mutation from their mother, they may have
gotten different doses of normal vs. mutant mtDNA, and the
mutant DNA may have distributed itself differently in their
DiMauro says that many doctors once discounted the idea
that mutations in the mtDNA could cause disease. Then, in
1988, it was discovered that mutations in mtDNA can lead to
disease and a torrential amount of research opened up.
Recently, interest in mitochondria has redoubled as
scientists find that mitochondrial dysfunction may be
involved in phenomena as diverse as diabetes, amyotrophic
lateral sclerosis (ALS) and aging.
There's no doubt that the resurgence of interest will yield
new information about mitochondrial disorders and their